Direct Reprogramming of Human Fetal- and Stem Cell-Derived Glial Progenitor Cells into Midbrain Dopaminergic Neurons
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- Direct Reprogramming of Human Fetal- and Stem Cell-Derived Glial Progenitor Cells into Midbrain Dopaminergic Neurons
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Human glial progenitor cells (hGPCs) are promising cellular substrates to explore for the in situ production of new neurons for brain repair. Proof of concept for direct neuronal reprogramming of glial progenitors has been obtained in mouse models in vivo, but conversion using human cells has not yet been demonstrated. Such studies have been difficult to perform since hGPCs are born late during human fetal development, with limited accessibility for in vitro culture. In this study, we show proof of concept of hGPC conversion using fetal cells and also establish a renewable and reproducible stem cell-based hGPC system for direct neural conversion in vitro. Using this system, we have identified optimal combinations of fate determinants for the efficient dopaminergic (DA) conversion of hGPCs, thereby yielding a therapeutically relevant cell type that selectively degenerates in Parkinson's disease. The induced DA neurons show a progressive, subtype-specific phenotypic maturation and acquire functional electrophysiological properties indicative of DA phenotype.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Stem Cell Reports |
| Vol/bind | 15 |
| Udgave nummer | 4 |
| Sider (fra-til) | 869-882 |
| Antal sider | 14 |
| ISSN | 2213-6711 |
| DOI | |
| Status | Udgivet - 2020 |
Bibliografisk note
Funding Information:
We thank Anna Hammarberg, Sol Da Rocha Baez, Jenny Johansson, Ulla Jarl, and Marie Persson Vejg?rden for excellent technical assistance; members of Steve Goldman's group at the University of Rochester for help with transferring the protocol for hESC-based generation of hGPCs to Lund; and Ernest Arenas for kindly providing virus plasmids. The research leading to these results has received funding from the New York Stem Cell Foundation (M. Parmar), the European Research Council (ERC grant agreement no. 771427, M. Parmar), the Swedish Research Council (grant agreements 2016-00873, M. Parmar; 2017-01234, D.R.O.), Swedish Parkinson Foundation (Parkinsonfonden, M. Parmar), Jeansson Foundation (Jeansson stiftelser, D.R.O.), Swedish Brain Foundation (Hj?rnfonden, M. Parmar), the Strategic Research Area at Lund University Multipark (Multidisciplinary research in Parkinson's disease), Knut och Alice Wallenberg Foundation (2018.0040, M. Parmar), National Institute of Neurological Disorders and Stroke (NINDS, S.A.G.), National Institute of Mental Health (NIMH, S.A.G.), ADELSON Medical Research Foundation (S.A.G.), Novo Nordisk Foundation (S.A.G.), Lundbeckfonden (S.A.G.), Oscine Corp. and Sana Biotechnology (S.A.G.). M. Parmar is a New York Stem Cell Foundation Robertson Investigator.
Funding Information:
We thank Anna Hammarberg, Sol Da Rocha Baez, Jenny Johansson, Ulla Jarl, and Marie Persson Vejgården for excellent technical assistance; members of Steve Goldman's group at the University of Rochester for help with transferring the protocol for hESC-based generation of hGPCs to Lund; and Ernest Arenas for kindly providing virus plasmids. The research leading to these results has received funding from the New York Stem Cell Foundation (M. Parmar), the European Research Council (ERC grant agreement no. 771427 , M. Parmar), the Swedish Research Council (grant agreements 2016-00873 , M. Parmar; 2017-01234 , D.R.O.), Swedish Parkinson Foundation (Parkinsonfonden, M. Parmar), Jeansson Foundation (Jeansson stiftelser, D.R.O.), Swedish Brain Foundation (Hjärnfonden, M. Parmar), the Strategic Research Area at Lund University Multipark (Multidisciplinary research in Parkinson's disease), Knut och Alice Wallenberg Foundation ( 2018.0040 , M. Parmar), National Institute of Neurological Disorders and Stroke (NINDS, S.A.G.), National Institute of Mental Health (NIMH, S.A.G.), ADELSON Medical Research Foundation (S.A.G.), Novo Nordisk Foundation (S.A.G.), Lundbeckfonden (S.A.G.), Oscine Corp. and Sana Biotechnology (S.A.G.). M. Parmar is a New York Stem Cell Foundation Robertson Investigator.
Publisher Copyright:
© 2020 The Authors
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